EWS-FLI-1 expression triggers a Ewing's sarcoma initiation program in primary human mesenchymal stem cells

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Ewing sarcoma family tumors (ESFT) are driven by the EWS-FLI-1 fusion gene from translocation t(11;22).
• The cellular origin and permissive environment for EWS-FLI-1 in ESFT pathogenesis remain largely unknown.
• EWS-FLI-1 typically induces growth arrest or apoptosis in differentiated cells.

Purpose of the Study:

• To identify the cell type that supports EWS-FLI-1 expression and function in ESFT.
• To investigate the role of EWS-FLI-1 in early ESFT development.
• To uncover key genes involved in ESFT pathogenesis.

Main Methods:

• Expression of EWS-FLI-1 in human mesenchymal stem cells (hMSC).
• Analysis of gene expression profiles in EWS-FLI-1 expressing hMSCs.
• Functional studies of candidate genes, including EZH2, in ESFT.

Main Results:

• EWS-FLI-1 expression is stably maintained in hMSCs without inhibiting proliferation.
• EWS-FLI-1 induces a gene expression profile highly similar to ESFT, including key discriminators.
• The polycomb group gene EZH2 is upregulated by EWS-FLI-1 and plays a critical role in ESFT growth.

Conclusions:

• Human mesenchymal stem cells (hMSCs) are a permissive cellular environment for EWS-FLI-1.
• hMSCs are candidate cells of origin for ESFT.
• EZH2 is a critical therapeutic target in Ewing sarcoma.